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( 12 ) United States Patent US009856497B2 (12 ) United States Patent ( 10 ) Patent No. : US 9 ,856 ,497 B2 Qi et al. (45 ) Date of Patent: Jan . 2 , 2018 ( 54 ) CHIMERIC PROTEINS AND METHODS OF 9 , 593 , 338 B2 3 / 2017 Liu et al . REGULATING GENE EXPRESSION 9 ,624 ,554 B2 4 /2017 Collins et al . 2004 /0197346 Al 10 / 2004 O 'Hare et al. 2006 /0182741 A1 8 / 2006 Bourel et al. @( 71 ) Applicant: THE BOARD OF TRUSTEES OF 2007 /0224615 Al 9 /2007 Lee et al. THE LELAND STANFORD JUNIOR 2007 /0231319 A1 10 /2007 Yednock et al. UNIVERSITY , Stanford , CA (US ) 2008 /0274913 AL 11 / 2008 Lee 2010 / 0076057 A1 3 / 2010 Sontheimer et al. 2010 / 0093617 AL 4 / 2010 Barrangou et al. @( 72 ) Inventors : Lei S . Qi, Stanford , CA (US ) ; P . C . 2011 / 0217739 AL 9 / 2011 Terns et al . Dave P . Dingal, Stanford , CA (US ) 2012 / 0077706 A1 * 3 / 2012 Lee . .. .. .. .. C12N 15 / 1055 506 / 11 @( 73 ) Assignee : The Board of Trustee of the Leland 2013 /0011828 A1 1 / 2013 Barrangou et al. Stanford Junior University , Stanford , 2014 / 0068797 Al 3 / 2014 Doudna et al. CA (US ) 2014 /0113376 Al 4 /2014 Sorek et al. 2014 /0179770 A1 * 6 /2014 * ZhangLilang . C12N 15 / 86 @ 514 /44 R ( * ) Notice: Subject to any disclaimer, the term of this 2014 /0199767 Al 7 / 2014 Barrangou et al . patent is extended or adjusted under 35 2014 /0234851 A1 8 / 2014 Leonard et al. U . S . C . 154 (b ) by 0 days . 2014 /0271635 Al 9 /2014 Brogdon et al . 2014 /0273226 AL 9 /2014 Wu ( 21 ) Appl. No .: 15 /403 , 058 2014 / 0294773 A1 10 / 2014 Brouns et al. 2014 /0295556 Al 10 /2014 Joung et al. 2014 / 0295557 A1 10 /2014 Joung et al . (22 ) Filed : Jan . 10 , 2017 2014 / 0315985 A 10 / 2014 May et al . 2014 /0342456 AL 11 /2014 Mali et al . (65 ) Prior Publication Data 2014 /0342457 AL 11/ 2014 Mali et al . 2014 /0342458 A1 11 /2014 Mali et al . US 2017 /0198308 A1 Jul. 13, 2017 (Continued ) Related U . S . Application Data FOREIGN PATENT DOCUMENTS ( 60 ) Provisional application No . 62/ 277 , 322 , filed on Jan . 11 , 2016 , provisional application No . 62 /351 ,522 , CA 2619833 Al 3 / 2007 filed on Jun . 17 , 2016 , provisional application No . EP 1916903 B1 7 /2010 62 /399 ,902 , filed on Sep . 26 , 2016 . (Continued ) (51 ) Int. CI. OTHER PUBLICATIONS CO7H 21/ 04 (2006 .01 ) ( 2006 .01 ) Cheng et al ( Cell Research , 2013 , 23 : 1163 - 1171 ). * C12N 15 / 90 Chavez et al (Nature Methods, 2015 , 12 : 326 - 310 ). * C12N 9 / 22 ( 2006 .01 ) Nunez et al ( ACS Chem . Biol .; Feb . 9 , 2016 ; 11: 681 -688 ). * ( 52 ) U .S . CI. Invitrogen “ TangoTM GPR21 - bla U2OS Cell -based Assay , " printed CPC .. .. C12N 15 / 907 (2013 .01 ) ; C12N 9 /22 2010 , p . 1 - 12 . ( 2013 .01 ) ; C12Y 301/ 00 (2013 .01 ) Lim et al (Nature Reviews, 2010 , 11 : 393 -403 ) * ( 58 ) Field of Classification Search Daringer et al (ACS Synthetic Biology , 2014 , 3 :892 - 902 ) .* None Wehr et al ( Chapter 8 ; G protein - Coupled Receptor Screening See application file for complete search history . Assays , Methods in Molecular Biology , Jan . 2015 ; vol. 1272 , p . 107 - 118 ). * (56 ) References Cited Qi et al ( Cell, 2013, 152 : 1173 - 1183 ) .* U . S . PATENT DOCUMENTS (Continued ) 5 , 888 , 813 A 3 / 1999 Endl et al. 7 , 049 , 076 B2 . 5 / 2006 Lee et al . Primary Examiner — Laura B Goddard 8 , 017 , 398 B2 9 / 2011 Lee et al. 8 , 546 , 553 B2 10 / 2013 Terns et al . (74 ) Attorney , Agent, or Firm — Kilpatrick Townsend & 8 , 697, 359 B1 4 / 2014 Zhang Stockton LLP 8 ,771 , 945 B1 . 7 / 2014 Zhang 8 , 795 , 965 B2 8 / 2014 Zhang 8 , 865 ,406 B2 10 / 2014 Zhang et al. (57 ) ABSTRACT 8 ,871 ,445 B2 10 / 2014 Le Cong et al . 8 , 889 , 356 B2 11/ 2014 Zhang The present disclosure provides systems, compositions and 8 , 895 ,308 B1 11/ 2014 Zhang et al. 8 , 906 , 616 B2 12 / 2014 Zhang et al. methods for regulating expression of a target polynucleotide 8 , 932 , 814 B2 1 /2015 Le Cong et al. in a cell. The systems, compositions and methods comprise 8 , 945, 839 B2 2 / 2015 Zhang a chimeric receptor polypeptide comprising a G -protein 8 , 993 , 233 B2 3 / 2015 Zhang et al. 8 , 999 , 641 B2 4 / 2015 Zhang et al. coupled receptor (GPCR ) or a fragment thereof, a chimeric 9 , 023 , 649 B2 5 / 2015 Mali et al . adaptor polypeptide, at least one actuator moiety and a 9 , 234 , 213 B2 1 / 2016 Wu cleavage moiety . 9 , 260 , 752 B1 2 / 2016 May et al. 9 , 580, 480 B2 2 / 2017 Lu et al. 9 , 587, 020 B2 3 /2017 Wu et al . 30 Claims, 49 Drawing Sheets US 9 ,856 ,497 B2 Page 2 References Cited WO 2015139139 9 / 2015 ( 56 ) WO 2015142661 9 /2015 U . S . 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